An Oral Selective M3 Anticholinergic Receptor Antagonist in COPD

¹ Depts of Respiratory and Allergy
² Biostatistics, Merck Research Laboratories, Rahway, New Jersey, USA

^* To whom correspondence should be addressed. E-mail: theodore_reiss{at}merck.com.

	Abstract

Anticholinergic antagonists have been used for a century as bronchodilators for COPD. This study investigated whether an oral M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD.

A 6-week, multicenter, randomized, placebo- and active-controlled, parallel-group study was performed at 56 sites in the United States. Four hundred twelve male and female patients (ages 35-86 yr) with a clinical history consistent with COPD were randomized to receive OrM3 0.5, 2, 3, or 4 mg orally once daily; ipratropium bromide 36 µg by inhalation 4 times daily; or placebo.

OrM3 demonstrated a significant dose-related improvement in serial FEV₁ and a trend for dose-related improvement in patient-reported symptoms compared with placebo. However, at a dose that provided efficacy less than that of ipratropium, the incidence of dose-related, mechanism-based side effects for OrM3 exceeded those observed for ipratropium.

In patients with COPD, OrM3 did not offer a therapeutic advantage over inhaled ipratropium. These results do not support the hypothesis that high selectivity for M3 receptors over airway neuronal M2 receptors will represent a more effective therapy than current inhaled anticholinergics in obstructive airway disease.